The n e w e ng l a n d j o u r na l of
review article
From the Department of Pathology, Co-
lumbia University College of Physicians
and Surgeons (V.D.D.); and the Division
of Pediatric Nephrology, Albert Einstein
College of Medicine (F.J.K.) — both in
New York; and UNC Kidney Center and
the Division of Nephrology and Hyper-
tension, University of North Carolina,
Chapel Hill (R.J.F.). Address reprint re-
quests to Dr. D’Agati at Columbia Univer-
sity Medical Center, Division of Renal
Pathology, Rm. VC14-224, 630 W. 168th
St., New York, NY 10032, or at vdd1@
columbia.edu.
N Engl J Med 2011;365:2398-411.
Copyright © 2011 Massachusetts Medical Society.
2398
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m e dic i n e
Medical Progress
Focal Segmental Glomerulosclerosis
Vivette D. D’Agati, M.D., Frederick J. Kaskel, M.D., Ph.D., and Ronald J. Falk, M.D.
F
ocal segmental glomerulosclerosis accounts for approximately
20% of cases of the nephrotic syndrome in children and 40% of such cases in
adults, with an estimated incidence of 7 per 1 million.1 It is the most common
primary glomerular disorder causing end-stage renal disease in the United States,
with a prevalence of 4%.2 The cardinal feature is progressive glomerular scarring.
Early in the disease course, glomerulosclerosis is both focal, involving a minority
of glomeruli, and segmental, affecting a portion of the glomerular globe. With pro-
gression, more widespread and global glomerulosclerosis develops. Since the first
clinical–pathological studies of the disease in the 1970s,3 there has been renewed
interest because of the increasing incidence of the disease,4 better understanding of
causation, and identification of the podocyte as the major cellular target.5 The dis-
covery that mutations in podocyte genes are associated with genetic focal segmen-
tal glomerulosclerosis has advanced the field of podocyte biology and stimulated new
approaches to diagnosis and management.6
Cl inic a l Fe at ur e s
Proteinuria is a defining feature of focal segmental glomerulosclerosis, typically
accompanied by hypoalbuminemia, hypercholesterolemia, and peripheral edema.
The nephrotic syndrome in children is defined as proteinuria (>1 g of urine protein
per square meter of body-surface area per day), hypoalbuminemia (<2.5 g of albumin
per deciliter), hypercholesterolemia (>200 mg of total cholesterol per deciliter), and
edema. In adults, the nephrotic syndrome is defined as a urine protein level of more
than 3.5 g per day and an albumin level of less than 3.5 g per deciliter. Approxi-
mately 75 to 90% of children and 50 to 60% of adults with focal segmental glomeru-
losclerosis have the nephrotic syndrome at presentation.
Once considered a single disease, focal segmental glomerulosclerosis is now
viewed as a group of clinical–pathologic syndromes sharing a common glomerular
lesion and mediated by diverse insults directed to or inherent within the podocyte
(Table 1). Despite the identification of many factors that lead to focal segmental
glomerulosclerosis, approximately 80% of cases are primary (idiopathic). Focal seg-
mental glomerulosclerosis and a related disorder, minimal change disease, are quint-
essential podocyte diseases, or “podocytopathies.”7,8 In both conditions, podocyte
injury leads to effacement of the podocyte foot processes, which is the major struc-
tural correlate of nephrotic proteinuria. This change in podocyte shape requires
rearrangement of the actin cytoskeleton, a process that is typically reversible with
glucocorticoid therapy in minimal change disease but irreversible and progressive
in focal segmental glomerulosclerosis.
n engl j med 365;25  nejm.org  december 22, 2011
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 medical progress

Table 1. Causes of Focal Segmental Glomerulosclerosis.

Type of Disease Cause

Primary (idiopathic) form Specific cause unknown; mediated by circulating permeability factors
Secondary forms
Familial or genetic Mutations in specific podocyte genes*
Virus-associated Human immunodeficiency virus type 1, parvovirus B19, simian virus 40, cytomegalovirus, Epstein–Barr virus
Drug-induced Heroin; interferons alfa, beta, and gamma; lithium; pamidronate; sirolimus; calcineurin-inhibitor nephrotoxicity;
anabolic steroids
Adaptive† Conditions with reduced renal mass: oligomeganephronia, very low birth weight, unilateral renal agenesis, renal
dysplasia, reflux nephropathy, sequela to cortical necrosis, surgical renal ablation, renal allograft, aging kid-
ney, any advanced renal disease with reduced functioning nephrons
Conditions with initially normal renal mass: systemic hypertension, acute or chronic vaso-occlusive processes
(atheroembolization, thrombotic microangiopathy, renal-artery stenosis), elevated body-mass index (obesity,
increased lean body mass [e.g., bodybuilding]), cyanotic congenital heart disease, sickle cell anemia

* For details regarding genetic mutations associated with focal segmental glomerulosclerosis, see the table in the Supplementary Appendix.
† The adaptive form is mediated by adaptive structural–functional responses to glomerular hypertension caused by elevated glomerular capil-
lary pressures and flows.

Podocyte Depletion in Experimental Toxin

Patho gene sis
Loss of Filtration Barrier
Nephrotic proteinuria results from loss of integ-
rity of the glomerular filtration barrier, which reg-
ulates permselectivity through the intimate as-
sociation of three layers: fenestrated glomerular
endothelial cells at the inner blood interface, the
glomerular basement membrane in the center, and
podocytes (also known as visceral epithelial cells)
at the outer urinary interface (Fig. 1). Podocytes
are highly differentiated, polarized epithelial cells
resembling neurons in their large cell body and
elongated cellular extensions, stabilized by a cen-
tral actin cytoskeleton core (Fig. 2). The foot pro-
cesses interdigitate along the outer aspect of the
glomerular capillary wall, linked to their neigh-
bors by slit diaphragms, which are modified ad-
herens junctions aligned in a zipperlike array.9
Podocytes provide structural support to the glo-
merular capillaries and synthesize the proteins
of the slit diaphragm and many extracellular ma-
trix components of the glomerular basement mem-
brane. These terminally differentiated cells cannot
repair by means of cell division, making podo-
cyte depletion through detachment, apoptosis, or
necrosis a critical mediator of glomerulosclerosis.8
In the past decade, new insights have derived both
from animal models of podocyte depletion and
genetic studies of human disease.
Models
Experimental models have addressed whether de-
livery of a lethal toxin specifically and exclusively
to the podocyte is sufficient to cause focal seg-
mental glomerulosclerosis. For example, the cre-
ation of a transgenic animal that expresses a toxin
receptor under the control of a podocyte-specific
promoter permits the targeting of a toxin exclu-
sively to podocytes.10,11 In such a model, inter-
nalization of diphtheria toxin or pseudomonas
exotoxin A kills podocytes by the inhibition of pro-
tein synthesis. The degree of podocyte depletion
after toxin exposure correlates closely with the se-
verity of disease in these models.11 Loss of more
than 40% of podocytes leads to overt focal seg-
mental glomerulosclerosis with high-grade pro-
teinuria and renal insufficiency, indicating a dis-
ease threshold.11 Podocytes are shed into the urine
for months after a brief toxin exposure, suggest-
ing a secondary autonomous phase of podocyte
loss.12 In a chimeric model in which only a sub-
set of podocytes express toxin receptor, podocyte
injury and dedifferentiation are observed to spread
to neighboring toxin-resistant podocytes that es-
caped the initial insult.13 This chimeric model sug-
gests that injury can propagate locally from podo-
cyte to podocyte by a domino-like effect, which
may explain the segmental nature of the lesions.
Although the mediators are unknown, a second-

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 The n e w e ng l a n d j o u r na l
ary wave of podocyte injury hypothetically might
decrease podocyte survival factors that signal
through nephrin and glutamate receptors14 or
might increase noxious factors, such as shear
stress, angiotensin II, or transforming growth fac-
tor β (TGFβ).13
An experimental model of focal segmental glo-
merulosclerosis that is induced by the anthracy-
cline doxorubicin (also called adriamycin) causes
severe disease in BALB/c mice, whereas other
mouse strains are protected. The strain depen-
dence went unexplained until the recent discov-
ery of the susceptibility gene as an ancestral mu­
tation in Prkdc (protein kinase, DNA-activated,
catalytic polypeptide), which encodes a compo-
nent of the DNA double-strand break-repair ma-
chinery.15 In BALB/c mice, there is no nonhomolo-
gous end-joining DNA repair after intercalation
of doxorubicin into podocyte DNA, leading to mi-
tochondrial DNA depletion.15 This murine model
illustrates the importance of protective mecha-
nisms against genotoxic stress to enhance podo-
cyte longevity.
Genetic Susceptibility
Since the discovery of nephrin as the major com-
ponent of the slit diaphragm in 1998,16 the num-
ber of identified podocyte mutations in familial
and sporadic focal segmental glomerulosclerosis
has grown (Fig. 2, and the table in the Supple-
mentary Appendix, available with the full text of
this article at NEJM.org). The genes encode di-
verse podocyte products located in the slit dia-
phragm,16-19 cell membrane,20-24 cytosol,25 actin
cytoskeleton,26-29 nucleus,30,31 mitochondria,32-34
and lysosomes.35 Mutations in nephrin and podo-
cin are the most frequent.36 Most mutations fol-
low an autosomal recessive transmission and man-
ifest early in life. Autosomal dominant forms (e.g.,
mutations in genes encoding α-actinin-4 and tran-
sient receptor potential cation channel 6) usually
present in late adolescence or adulthood. Many of
the genes that are involved were identified by po-
sitional cloning in affected families and later vali-
dated in global or podocyte-specific knockout
models or in transgenic models that express the
mutated genes. Genetic defects have been identi-
fied in up to two thirds of patients with focal
segmental glomerulosclerosis who present in the
first year of life, underscoring the importance of
genetic testing in this age group.37 Genetic test-
2400 n engl j med 365;25  nejm.org  december 22, 2011
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of m e dic i n e
Figure 1 (facing page). Morphogenesis of Focal Seg-
mental Glomerulosclerosis (FSGS).
The sequence of glomerular changes in the develop-
ment of FSGS is illustrated by parallel light-microscop-
ic and electron-microscopic images. The normal glo-
merular capillaries are widely patent and have intact
foot processes (or pedicels) along their outer aspect.
Podocytes that are targeted by cellular stresses, such
as permeability factors (external causes) or disease-
causing mutations (intrinsic defects), respond by the
reorganization of their actin cytoskeleton, leading to
foot-process effacement. This change in cell shape
forms a sheet of undifferentiated cytoplasm over the
surface of the glomerular basement membrane. If the
inciting injurious factors are long-standing or the podo-
cyte is exposed to second hits, a critical level of cell
stress is reached and the injured or dying podocyte
­detaches from the glomerular basement membrane.
Because podocytes are unable to repair by cell division,
attrition of a finite number of podocytes leads to scle-
rosis of the underlying glomerular capillaries, which
become obliterated by matrix. At these sites, adhesions
to Bowman’s capsule may form, and parietal cells often
migrate onto the tuft, where they lay down loose matrix
material. In the early stages, the sclerotic lesions are
typically segmental, involving a portion of the glomeru-
lar tuft.
ing is most likely to uncover a basis for focal seg-
mental glomerulosclerosis in infants, young chil-
dren, and patients with syndromic disease or a
positive family history. A small but clinically im-
portant percentage of older children and adults
with sporadic glucocorticoid-resistant disease may
also harbor mutations.36
Podocyte genes encode diverse structural pro-
teins or enzymes that participate in signaling
events that regulate podocyte growth, differentia-
tion, motility, and interactions between cells and
between cells and matrix.38 These gene products
are coupled to the actin cytoskeleton directly or
indirectly through intermediary proteins (Fig. 2).
Disruption or dysregulation of signaling through
these proteins leads to rearrangement of the actin
cytoskeleton and the generalized response of foot-
process effacement. The podocyte is a motile cell
endowed with mechanosensors that respond to
positional stimuli and shear stress.39 Factors that
promote the development of a cytoskeleton that
is either too rigid or too dynamic pose potential
threats to podocyte survival. For example, disease-
causing mutations in α-actinin-4 produce a rigid
cytoskeleton by exposing a buried actin-binding
 medical progress

Normal glomerulus with intact foot processes

Foot-process effacement

Podocyte detachment

FSGS with parietal-cell coverage

Segmental sclerosis with podocyte loss

site that is independent of calcium regulation,
leading to a gain of function.40 Once the actin cy-
toskeleton undergoes rearrangement, the loss of
foot-process anchoring may weaken podocyte at-
tachments to the glomerular basement membrane,
rendering them more vulnerable to detachment in
response to filtration pressures. It is likely that
the wear and tear from shear stress, stretch ten-
sion, oxidative stress, and DNA damage that ac-
crues over years may compound a genetic basis
for this disease.41 Such accumulated second hits
might explain the late onset of genetic focal seg-
mental glomerulosclerosis in adults with autoso-
mal dominant mutations.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Figure 2 (facing page). Normal Glomerulus and Glomerular Filtration Barrier.

In Panel A, each kidney contains approximately 1 million glomeruli, which comprise the filtering units of the kidney. The normal glomer-
ulus is composed of a specialized bundle of capillaries that originates from branchings of the afferent arteriole as it enters the hilus
(or vascular pole). Between the afferent and efferent arterioles, bordered by the macula densa of the distal tubule, is the triangular juxta-
glomerular apparatus, an endocrine organ involved in renin production and tubuloglomerular feedback. The glomerular capillaries are
supported by the mesangial cells, which are invested in matrix and are continuous with the smooth-muscle cells of the hilar arterioles.
The glomerular endothelial-cell bodies are oriented toward the mesangium, whereas their fenestrated cytoplasm lines the inner aspect
of the peripheral glomerular basement membrane. The glomerular basement membrane forms a scaffold for the glomerular capillaries
and reflects over the mesangium. Along their outer aspect, the glomerular capillaries are supported by the podocytes, which reside in
the urinary space and have interdigitating foot processes. The glomerular ultrafiltrate enters the urinary space and passes into the tubu-
lar pole (the origin of the proximal tubule), which lies opposite the vascular pole. In Panel B, the glomerular capillary wall and selected
components of the filtration barrier are shown. On the urinary side, the interdigitating podocyte foot processes are aligned in regular ar-
rays separated by filtration slit diaphragms located above the glomerular basement membrane. The fenestrated glomerular endothelium
is present at the blood interface. The inset diagrams show some of the molecules that make up the slit diaphragm (above) and the basal
surface of the podocyte (below). Nephrin is the major component of the slit diaphragm. Pairs of nephrin molecules extending out into
the center of the slit from adjacent podocyte foot processes form homophilic interactions as well as heterophilic interactions with
NEPH. The slit diaphragm complex includes podocin, which forms a hairpin turn within the podocyte membrane. Through interaction
with CD2-associated protein (CD2AP), the slit diaphragm molecules are linked to the actin cytoskeleton, which is regulated by
α-actinin-4, inverted formin 2 (INF2), and myosin 1E (Myo1E). Calcium generated by phospholipase C epsilon 1 (PLCε1) through diacyl-
glycerol (DAG) and inositol triphosphate (IP3) and entering the cell through transient receptor potential cation channel 6 (TRPC6) regu-
lates actin polymerization. At the basal surface, adhesion molecules α3 β1 integrin and α-dystroglycan are linked to laminin. Integrin is
coupled to the actin cytoskeleton through a complex of talin, vinculin, and paxillin, whereas adhesion molecule α-dystroglycan links to
actin through utrophin. Negatively charged molecules podocalyxin and glomerular epithelial protein 1 (GLEPP-1) are arrayed on the api-
cal-cell membrane.

Genetic Basis in Patients of African Descent
Across age groups, the incidence of focal segmen-
tal glomerulosclerosis is higher and the rate of
renal survival is worse among blacks than among
whites. Mapping by means of admixture linkage
disequilibrium in large populations identified ge-
netic risk factors for focal segmental glomerulo-
sclerosis and end-stage renal disease in blacks.
Two genes in close linkage disequilibrium were
identified on human chromosome 22. MYH9, en-
coding myosin heavy chain 9, a nonmuscle myosin
IIA that is a component of the podocyte cytoskel-
eton, was identified first42 and was an attractive
candidate because MYH9 mutations were known
to cause a rare autosomal dominant form of focal
segmental glomerulosclerosis in patients with Ep-
stein–Fechtner syndromes (renal disease, sensori-
neural deafness, and macrothrombocytopenia).27,43
Genomewide scans identified three single-nucle-
otide polymorphisms in intron 23 of the MYH9
gene as conferring risk for primary focal segmen-
tal glomerulosclerosis and hypertensive end-stage
renal disease among blacks in an autosomal re-
cessive model.42,44 However, further probing of
the genetic interval found two independent se-
quence variants (called G1 and G2) in the last
exon of the neighboring gene encoding apolipo-
protein L1 (APOL1) that had a stronger association
with focal segmental glomerulosclerosis, with a
combined signal that was increased by a factor of
35 over that of MYH9. Thus, APOL1 was implicat-
ed as the actual susceptibility gene.45
Selection tests in Europeans and Africans
showed that the APOL1 G1 and G2 haplotypes
were under strong selection only in Africa.45 Apo-
lipoprotein L1 is a plasma factor that can lyse
Trypanosoma brucei brucei, the parasite that causes
sleeping sickness. Two subspecies of trypanosoma
that are resistant to lysis by apolipoprotein L1,
T. brucei rhodesiense and T. brucei gambiense, evolved
in sub-Saharan Africa. The G1 and G2 variants of
APOL1 lyse T. brucei rhodesiense, but not T. brucei
gambiense, a finding that explains how these vari-
ants could have risen to high frequency by natu-
ral selection. This scenario is analogous to sickle
cell trait, in which a mutation in the hemoglobin
A beta chain confers protection against malaria
but at the risk of hemoglobinopathy. In both situ-
ations, the protection against parasitic infection is
a dominant trait present in heterozygotes, whereas
the development of host disease is a recessive
trait, present in homozygotes. How the APOL1 G1
and G2 variants act mechanistically on the podo-
cyte to cause focal segmental glomerulosclerosis
has not been delineated.
Pathol o gic a l Defini t ion
The histologic definition of focal segmental glo-
merulosclerosis is a segmental obliteration of

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 medical progress

A
Proximal tubule
Tubular pole GLEPP-1
IP3
Bowman’s Podocyte-cell body
capsule PLCε1 Ca
2+

Urinary Parietal
space epithelial cell Podocalyxin DAG
2+
Ca
Endothelial-
cell body TRPC6 Myo1E
Podocin Nephrin

Glomerular Actinin
CD2AP
capillary lumen
NEPH
Mesangial Mesangial cell
matrix Slit diaphragm INF2
Actin
Podocyte-
cell membranes Foot-process cytoplasm
Glomerular
basement
membrane
Basal
Fenestrated Podocyte podocyte Actin
Vascular endothelium foot process cytoplasm
Actinin
pole (hilus) Juxtaglomerular Utrophin
apparatus
Podocyte- Vinculin Paxillin
Afferent Efferent cell Talin
arteriole arteriole membrane
Macula densa Integrin CD151 α-dystroglycan
of distal tubule
α3 β1
Glomerular
B basement
membrane Laminin

Collagen IV

Slit
diaphragm
Podocyte foot
process

Glomerular basement membrane

Endothelium

Fenestra

COLOR FIGURE

glomerular capillaries by extracellular matrix.7,46 matrix material synthesized by parietal cells Draft
that14 12/01/11
Author D’Agati
Entrapment of plasma proteins as hyalinosis com- migrate onto the tuft, producing a halolikeFigeffect.
# 2
monly accompanies the sclerosis. Because juxta- Granular immune-type electron-dense deposits Title are

medullary nephrons are often affected first, ad- not present. Immunofluorescence typically reveals
ME
equate glomerular sampling is needed to identify coarse segmental staining for IgM and C3 DE en- Ingelfinger
Artist Knoper
the diagnostic lesions. Adhesions or synechiae may trapped in areas of hyalinosis. As individual neph- AUTHOR PLEASE NOTE:
form between the sclerosing segment and Bow- rons degenerate, tubular atrophy and interstitial
Figure has been redrawn and type has been reset
Please check carefully

man’s capsule. On electron microscopy, the major fibrosis develop. Proximal tubular reabsorption
Issue date 12/22/11

finding is extensive effacement of the foot pro-
cesses without other abnormalities in the glomer-
ular basement membrane. Detachment of podo-
cytes from the glomerular basement membrane
occurs in regions overlying the sclerotic lesions.
At these sites, there is often accumulation of loose
droplets reflect heightened tubular trafficking of
albumin and lipoproteins, a process that contrib-
utes to progressive tubulointerstitial injury.47
The pathologic diversity of glomerular lesions
in focal segmental glomerulosclerosis is evi-
dent.7,46,48 Lesions differ anatomically in their

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 The n e w e ng l a n d j o u r na l of m e dic i n e

location with respect to the glomerular hilus
(vascular pole) and the tubular pole and qualita-
tively with respect to glomerular hypercellularity
and capillary collapse.46 A classification of his-
tologic variants recognizes not-otherwise-speci-
fied (NOS),46 perihilar,46,49-53 cellular,53,54 tip,46,55,56
and collapsing disease57-62 variants and is appli-
cable to both primary and secondary focal seg-
mental glomerulosclerosis (Fig. 3).
In the collapsing variant, podocytes have an

Histologic
Subtype Glomerular Lesion Defining Features Associations Clinical Features

NOS The usual generic form of FSGS.
FSGS(NOS) does not meet defining
criteria for any other variant.
Foot-process effacement is variable.
Primary or secondary (including May present with the
genetic forms and other nephrotic syndrome
diverse secondary causes). or subnephrotic
Cross-sectional studies suggest proteinuria.
this is the most common
subtype.
Other variants can evolve into
FSGS (NOS) over time.

Perihilar Perihilar hyalinosis and sclerosis
involving the majority of glomeruli
with segmental lesions.
Perihilar lesions are located at the
glomerular vascular pole.
In adaptive FSGS, there is usually
glomerular hypertrophy (glomer-
ulomegaly).
Foot-process effacement is relatively
mild and focal, which probably
reflects the heterogeneous adap-
tive responses of glomeruli.
Common in adaptive FSGS In adaptive FSGS, patients
associated with obesity, ele- are more likely to pre-
vated lean body mass, reflux sent with subnephrotic
nephropathy, hypertensive proteinuria and normal
nephrosclerosis, sickle cell serum albumin levels.
anemia, and renal agenesis.
Predisposition for vascular pole
is probably due to normally
increased filtration pressures
at the proximal afferent end
of glomerular capillary bed,
which are heightened under
conditions of compensatory
demand and vasodilatation
of the afferent arteriole.

Cellular Expansile segmental lesion with
endocapillary hypercellularity,
often including foam cells and
infiltrating leukocytes, with
variable glomerular epithelial-
cell hyperplasia.
There is usually severe foot-process
effacement.
Usually primary, but also seen Usually presents with the
in a variety of secondary forms. nephrotic syndrome.
This is the least common variant.
It is thought to represent an early
stage in the evolution of
sclerotic lesions.

Tip Segmental lesion involving the
tubular pole, with either adhesion Probably mediated by physical
to tubular outlet or confluence
of podocytes and tubular epithelial
cells.
Compared with other variants, it
has the least tubular atrophy
and interstitial fibrosis.
There is usually severe foot-process
effacement.
Usually primary.
stresses on the paratubular
segment owing to the conver-
gence of protein-rich filtrate
on the tubular pole, causing
shear stress and possible
prolapse.
Usually presents with
abrupt onset of the
nephrotic syndrome.
More common in white
race.
Best prognosis, with high-
est rate of responsivity
to glucocorticoids and
lowest risk of progres-
sion.

Collapse Implosive glomerular-tuft collapse Primary or secondary to Most aggressive variant

with hypertrophy and hyperplasia Viruses: HIV-1, parvovirus of primary FSGS with
of the overlying visceral epithelial B19, SV40, EBV, CMV, black racial predomi-
cells. hemophagocytic syndrome nance and severe
Hyperplastic glomerular epithelial Drugs: pamidronate and nephrotic syndrome.
cells may fill the urinary space, interferon Worst prognosis, with
resembling crescents. Vaso-occlusive disease: athero- poor responsivity to
Severe tubular injury and tubular emboli, calcineurin inhibitor glucocorticoids and
microcysts are common. nephrotoxicity, and chronic rapid course to renal
There is usually severe foot-process allograft nephropathy failure.
effacement.

Figure 3. Histologic Variants of Focal Segmental Glomerulosclerosis (FSGS).

CMV denotes cy tomegalovirus, EBV Epstein–Barr virus, HIV-1 human immunodeficiency virus type 1, NOS not otherwise specified, and
SV40 simian virus 40.

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 medical progress
immature, dysregulated phenotype.63,64 Because
injured podocytes lose differentiation markers
such as nephrin, the identity of the cells that pro-
liferate in Bowman’s space has been controver-
sial. Recent studies using parietal-cell markers
suggest that most of these cells actually origi-
nate from the parietal layer.65-67 Moreover, pro-
genitor cells bearing stem-cell markers CD133
and CD24 line Bowman’s capsule, possibly serv-
ing as a reservoir to replenish lost podocytes.68
Although progenitor cells may be recruited to
sites of podocyte denudation, it is not known
whether they can differentiate into the mature
podocytes that are needed to reconstitute a nor-
mal filtration barrier.
Pr im a r y (Idiopathic) Dise a se
Primary focal segmental glomerulosclerosis has
long been attributed to a putative circulating per-
meability factor. Indirect evidence for a circulat-
ing plasma factor includes the ability to modu-
late proteinuria by immunoadsorption, potential
disease recurrence minutes after renal transplan-
tation, and therapeutic reduction in proteinuria
by plasmapheresis.69 In addition, serum samples
from patients with focal segmental glomerulo-
sclerosis cause increased permeability to albumin
in isolated glomeruli and induce foot-process ef-
facement and proteinuria when injected into rats.
Several candidate plasma factors have been pro-
posed. For example, cardiotrophin-like cytokine 1,
a member of the interleukin-6 family, has perme-
ability activity in a plasma fraction with a molecu-
lar weight of less than 30 kD and can be enriched
by means of galactose affinity chromatography.69
Elevated serum levels of soluble urokinase recep-
tor (>3000 pg per milliliter) have been identified
in up to two thirds of patients with primary focal
segmental glomerulosclerosis but not in those
with minimal change disease.70 Increased serum
levels of soluble urokinase receptor before renal
transplantation were associated with an increased
risk of recurrent disease in the allograft.70 Circu-
lating soluble urokinase receptor induces foot-
process effacement through the activation of podo-
cyte β3 integrin, and its effect can be blocked in
animal models by neutralizing antibodies target-
ing soluble urokinase receptor.70,71 The cellular
source and stimulants of soluble urokinase recep-
tor in patients with focal segmental glomerulo-
sclerosis are unknown.
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V irus-Induced Dise a se
Viruses can act on the podocyte either by direct
infection or by the release of inflammatory cyto-
kines that interact with podocyte receptors. The
best studied of such viruses is human immuno-
deficiency virus type 1 (HIV-1), which directly
infects podocytes and tubular epithelial cells.72
Evidence supports HIV-1 entry by transfer from
infected T cells to tubular epithelial cells through
virologic synapses formed during cell adhesion,
independent of CD4.73 HIV-1 can persist in the
kidney epithelium despite antiretroviral therapy
and normalization of peripheral CD4 counts.
HIV-1 gene expression by infected renal epithelium
in turn induces dysregulation of host genes. The
form of focal segmental glomerulosclerosis asso-
ciated with untreated HIV-1, called HIV-associated
nephropathy (HIVAN), typically progresses rap-
idly and is associated with glomerular collapse.62
In vivo and in vitro models have identified viral
genes nef and vpr as particularly important in
HIVAN pathogenesis.74,75 Nef, a virulence factor,
contains a proline-rich motif that interacts with
the SH3 domain of the Src family kinases. Through
downstream activation of STAT3 and MAPK1/2,
it promotes podocyte dedifferentiation and prolif-
eration, whereas interaction with diaphanous in-
teracting protein mediates the up-regulation of
Rac1, reduction in RhoA, and dysregulation of ac-
tin cytoskeleton.76 Vpr, which is required for nu-
clear entry of the HIV-1 preintegration complex,
mediates tubular epithelial G2 cell-cycle arrest
and apoptosis.77,78 Parvovirus B19 is another vi-
rus that can infect podocytes and tubular cells,
leading to collapsing focal segmental glomerulo-
sclerosis.60 Other viruses associated with this dis-
ease, such as simian virus 40, cytomegalovirus, and
Epstein–Barr virus, are less well characterized.57,61
Drug -Induced Dise a se
Historically, the first drug associated with focal
segmental glomerulosclerosis was heroin, though
the incidence of this drug-induced disease (known
as heroin nephropathy) has fallen sharply in par-
allel with the increasing purity of modern street
heroin.79 The bisphosphonate pamidronate, an
osteoclast inhibitor used to reduce bone resorp-
tion in patients with myeloma and metastatic can-
cers, has been linked to the development of focal
segmental glomerulosclerosis.58 Proteinuria and
2405
 The n e w e ng l a n d j o u r na l of m e dic i n e

renal failure associated with pamidronate typically
improve after withdrawal of the drug. Pamidro-
nate has direct toxic effects on osteoclasts, in-
cluding disruption of the actin cytoskeleton, sug-
gesting the possibility of a similar effect on the
podocyte cytoskeleton.
All forms of interferon therapy, including in-
terferon alfa (widely used to treat hepatitis C),
interferon beta (indicated for multiple sclerosis),
and interferon gamma (formerly used in idiopath-
ic pulmonary fibrosis and indicated for chronic
granulomatous disease and malignant osteope-
trosis), have been reported to induce focal seg-
mental glomerulosclerosis.59 The podocyte has
receptors for interferon alfa and interferon beta
and expresses major histocompatibility complex
class II antigen in response to interferon gamma,
suggesting potential direct podocyte effects. In
the transplanted kidney, toxic effects from calci-
neurin inhibitors are associated with collapsing
focal segmental glomerulosclerosis and hyaline
arteriolopathy, probably through acute ischemia
from severe vasoconstriction.80,81 In addition, the
mammalian target of rapamycin (mTOR) inhibi-
tor sirolimus (also known as rapamycin) can in-
duce focal segmental glomerulosclerosis by re-
ducing podocyte expression of critical proteins in
the slit diaphragm and cytoskeleton, including
nephrin.82
Dise a se Sec onda r y t o
Hemody na mic A da p tat ions
Another form of focal segmental glomeruloscle-
rosis, termed adaptive focal segmental glomeru-
losclerosis, is thought to result from structural
and functional adaptations mediated by intrare-
nal vasodilatation, increased glomerular capillary
pressures, and plasma flow rates.52 Such mal-
adaptive responses may arise through a reduction
in the number of functioning nephrons (e.g., in
unilateral renal agenesis, reflux nephropathy, or
low nephron endowment owing to very low birth
weight50) or through mechanisms that place he-
modynamic stress on an initially normal nephron
population (e.g., in morbid obesity, cyanotic con-
genital heart disease, and sickle cell anemia) (Ta-
ble 1). Unlike primary focal segmental glomeru-
losclerosis, adaptive disease is often associated
with normal serum albumin levels, despite ne-
phrotic-range proteinuria, and biopsy samples ob- A variety of clinical and pathologic features pre-
tained from such patients often show enlarged dict outcome. Black race, increased degrees of pro-
glomeruli, perihilar sclerosis, and relatively mild
degrees of foot-process effacement.7,46
Animal models in which renal mass is mark-
edly reduced have elucidated the mechanistic bases
for adaptive focal segmental glomerulosclerosis.83
Reflex vasodilatation of both the afferent and ef-
ferent arterioles follows a marked reduction in
renal mass, causing elevation in the flow rate in
the glomerular capillaries. Because the reduction
in vascular resistance is greater in the afferent
arteriole than in the efferent arteriole, glomerular
hydrostatic pressure rises, producing glomerular
hypertension. These responses cause an eleva-
tion in the single-nephron glomerular filtration
rate in proportion to the amount of kidney ex-
cised.52,83 Glomerular volume and surface area
increase, placing mechanical strain on podocytes
that stretch to cover the expanding tuft. Some
hypertrophied podocytes detach, producing de-
nuded patches of glomerular basement mem-
brane. These sites become covered by parietal
cells, leading to the formation of a synechia to
Bowman’s capsule and a nidus for the develop-
ment of segmental sclerosis.84
Although this scenario is the initiating step in
the adaptive forms of focal segmental glomeru-
losclerosis, it may supervene in the later stages of
other forms of the disease. The loss of a critical
number of nephrons promotes the activation of
the renin–angiotensin system (RAS), exacerbat-
ing proteinuria and setting the stage for progres-
sive glomerulosclerosis regardless of the initial
cause. Angiotensin II also has direct proapoptotic
effects on podocytes.85 Excessive protein uptake
by podocytes induces podocyte TGFβ,86 which
promotes apoptosis and leads to endoplasmic
reticulum stress, cytoskeletal reorganization, and
dedifferentiation.87 Drugs that are aimed at the
inhibition of RAS (such as angiotensin-convert-
ing–enzyme [ACE] inhibitors and angiotensin-
receptor blockers) lower intraglomerular filtration
pressures through the inhibition of angiotensin
II–mediated vasoconstriction of the efferent ar-
teriole. ACE inhibition also augments bradykinin,
which contributes to efferent arteriolar dilatation.
The resulting reduction in proteinuria exerts a
protective effect on podocytes and tubular cells.
Pro gnos t ic Fe at ur e s

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The New England Journal of Medicine

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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 medical progress
teinuria and renal insufficiency, and increased
severity of interstitial fibrosis and tubular atro-
phy in biopsy specimens are associated with a
worse outcome. Patients who have a partial or
complete remission of proteinuria have better out-
comes than those who do not.88 The histologic
variant also correlated with remission status and
outcome in two large case series,53,54 in which
rates of complete and partial remission were high-
est for the tip variant, were intermediate for the
cellular, perihilar, and NOS variants, and were
lowest for the collapsing variant. Renal survival
was inversely related to remission status, with the
best rates of renal survival in the tip variant and
the worst rates in the collapsing variant.53,54 The
prognosis in the adaptive form of the disease is
typically much better than in the primary form,
possibly as a consequence of an increased likeli-
hood of complete or partial remission with RAS
inhibition in this population.
Ther a py
The goal of therapy is to induce a complete or
partial remission of proteinuria and preserve re-
nal function. Even partial remission is associated
with improved long-term survival.89,90 The treat-
ment of primary focal segmental glomeruloscle-
rosis is empiric and based on the rationale that
the permeability factor derives from a dysregulat-
ed immune response. In addition, these therapies
have beneficial effects directly on podocytes.91
Children with the nephrotic syndrome are
treated empirically with oral prednisone (60 mg
per square meter of body surface per day) for 4 to
6 weeks, a regimen that is based on the statisti-
cal likelihood that most children (approximately
80%) will have glucocorticoid-responsive minimal
change disease. In most centers, usually only chil-
dren with glucocorticoid resistance are subjected
to renal biopsy. In contrast, adults with the ne-
phrotic syndrome usually undergo renal biopsy
before the initiation of therapy, since the possi-
ble causes are far more varied.
Once a diagnosis is established on biopsy, po-
tential secondary causes that require specific
therapies should be ruled out before a patient is
presumed to have primary focal segmental glo-
merulosclerosis. For example, the form of the
disease that is caused by HIV-1 infection is treat-
ed with antiretroviral therapy, and drug-induced
forms are managed by discontinuation of the in-
n engl j med 365;25  nejm.org  december 22, 2011
The New England Journal of Medicine
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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
citing agent. Patients with focal segmental glo-
merulosclerosis receive RAS blockade and dietary
sodium restriction as initial therapy. In the adap-
tive form of the disease, such therapy typically re-
sults in the diminution of proteinuria to less than
1 g per day. There is no evidence to support glu-
cocorticoid therapy in adaptive or genetic forms
of the disease. Some genetic forms may respond
to empirical therapy with calcineurin inhibitors.
An algorithm for the treatment of primary
focal segmental glomerulosclerosis is illustrated
in Figure 4. High-dose glucocorticoid therapy can
be given as 1 mg per kilogram of body weight
daily or as 2 mg per kilogram on alternate days.
In adults, a response to glucocorticoids may take
up to 16 weeks,92 after which the drugs can be
slowly tapered over a period of 3 to 6 months.
There is little evidence to recommend glucocor-
ticoid therapy in patients with the primary form
of the disease that is not accompanied by the
nephrotic syndrome. Therapy for glucocorticoid-
resistant focal segmental glomerulosclerosis is a
calcineurin inhibitor, either cyclosporine93 or tac­
rolimus. In some patients, such as those with
diabetes, a psychiatric disorder, or severe osteo-
porosis, concern about the side effects of gluco-
corticoid therapy may prompt the selection of a
calcineurin inhibitor alone as first-line therapy.
Cyclosporine can be given in divided doses of 3 to
5 mg per kilogram per day for 4 to 6 months to
induce remission. Patients are more likely to re-
main in remission if calcineurin inhibitor therapy
is continued for at least 12 months before slowly
tapering. In addition to the systemic immunosup-
pressive properties of glucocorticoids and calci-
neurin inhibitors, these drugs exert direct effects
on the podocyte that enhance prosurvival path-
ways and stabilize the actin cytoskeleton.91,94 The
control of blood pressure and hyperlipidemia is
also a critical element of supportive care.
A randomized trial was conducted in glucocor-
ticoid-resistant children and adults up to 40 years
of age comparing a 12-month course of cyclo-
sporine therapy with a combination of oral pulse
dexamethasone and mycophenolate mofetil.95 Par-
tial or complete remission occurred in 46% of the
cyclosporine group versus 33% of the group re-
ceiving dexamethasone–mycophenolate mofetil,
a difference that was not statistically significant.
Although somewhat underpowered, this study
suggests that these regimens have limited addi-
tional benefit in glucocorticoid-resistant patients
2407
 The n e w e ng l a n d j o u r na l of m e dic i n e

FSGS

Primary FSGS Primary FSGS with the

Secondary FSGS
with subnephrotic nephrotic syndrome or Adaptive FSGS
(e.g., viral, drug-induced)
proteinuria nephrotic-range proteinuria

RAS inhibition and dietary Glucocorticoids daily or alternate RAS inhibition and dietary Treatment of underlying cause
sodium restriction day and RAS inhibition sodium restriction whenever possible

Children, Adults,
4–6 wk of 16 wk of
treatment treatment
No response or worsening or
disease

Calcineurin inhibition
Glucocorticoid-resistant FSGS
(if glucocorticoid intolerance,
osteoporosis, other contra-
indications to glucocorticoids)

Calcineurin inhibition

Figure 4. Treatment Algorithm for Focal Segmental Glomerulosclerosis (FSGS).

RAS denotes renin–angiotensin system.

and shows the potential for toxicity from large

doses of glucocorticoids.
Glucocorticoid and calcineurin inhibitor ther-
apies are successful in approximately 50% of pa-
tients. Other therapies have been tried, including
alkylating agents, plasmapheresis, and even the
anti–B-cell monoclonal antibody rituximab, which
also stabilizes the podocyte actin cytoskeleton,96
but none of these therapies have been shown to
be effective. Sirolimus has been associated with
adverse events, including acute renal failure.97
Most patients with progressive focal segmen-
tal glomerulosclerosis have persistent nephrotic-
range proteinuria. Although patients with non-
nephrotic proteinuria are at a reduced risk for
progression to end-stage renal disease, sustained
non-nephrotic proteinuria is associated with an
increased risk of death and complications from
cardiovascular causes.98 Thus, the control of hy-
pertension, hyperlipidemia, and edema is impor-
tant in risk management.
R ecur r ence a f ter K idne y
T r a nspl a n tat ion
In approximately 40% of patients with primary
focal segmental glomerulosclerosis with end-stage
renal disease who undergo kidney transplantation,
recurrent disease develops in the allograft. Risk
factors for recurrence include younger age (espe-
cially in children 6 to 15 years of age), nonblack
race, a rapid course to end-stage renal disease
(<3 years) in the native kidney, heavy proteinuria
in the period before transplantation, and the loss
of previous allografts to recurrence.99 Early re-
current focal segmental glomerulosclerosis resem-
bles minimal change disease with extensive foot-
process effacement, but repeat biopsy samples
show evolution to lesions associated with focal
segmental glomerulosclerosis over time. In such
cases, the histologic subtype is the same as that
in the native kidney in approximately 80% of pa-
tients, supporting the persistence of a similar

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The New England Journal of Medicine

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Copyright © 2011 Massachusetts Medical Society. All rights reserved.
 medical progress

pathogenesis.100 Plasmapheresis to remove the pu-
tative permeability factor is most beneficial early
in the course of recurrence and is reported to lead
to remission after 8 to 12 treatments.99
C onclusions
Focal segmental glomerulosclerosis is a common
pattern of glomerular disease comprising diverse
clinical and pathologic syndromes. All forms of
the disease share podocyte injury and depletion
as central mediators of the pathology. Great
progress has been made in unraveling the patho-
genesis of genetic and secondary forms. Advanc-
es in identification of the permeability factors
causing the common primary form hold promise
for the design of more targeted therapies.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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